Inhibition of HSPA8 by rifampicin contributes to ferroptosis via enhancing autophagy

Zhou, Juan1; Tan, Yingzheng1; Hu, Lingli1; Fu, Jingli1; Li, Dan1; Chen, Jun2; Long, Yunzhu1

2022-10-01

10.1111/liv.15459

LIVER INTERNATIONAL   Impact Factor & Quartile

1478-3223

1478-3231

Background and Aim Rifampicin is the most common pathogenic factor in anti-tuberculosis drug-induced liver injury (AT-DILI), the mechanisms that it promotes hepatocyte damage in AT-DILI are not yet to be thoroughly elucidated. In this study, we investigated the potential molecular mechanisms for ferroptosis involving rifampicin hepatotoxicity. Methods Animal and cell injury models of rifampicin were constructed, and the toxicity of rifampicin was assessed by physicochemical staining and cell viability assay. Next, flow cytometry was employed to detect changes in ferroptosis-related markers, and Western blotting was used to detect protein expression. Then, the important role of autophagy and ferroptosis was verified with small molecule compound intervention. Results We found that ferritinophagy-induced ferroptosis participates in the toxicity of rifampicin, and the mechanism is that rifampicin precisely activates high-throughput autophagy, which leads to the massive degradation of ferritin and the increase of free iron. Moreover, rifampicin exhibited conspicuous inhibition of Human 71 kDa heat shock cognate protein (HSPA8) that is intimately associated with Microtubule-associated protein light chain 3 isoform B (LC3B) expression, in turn, HSPA8 inducer attenuated intracellular autophagy flux. Of note, inducing HSPA8 or inhibition of autophagy and ferroptosis considerably relieved the hepatotoxicity of rifampicin in mouse model. Conclusions The present study highlights the crucial roles of the HSPA8 and autophagy in ferroptotic cell death driving by rifampicin, particularly illumines multiple promising regulatory nodes for therapeutic interventions in diseases involving AT-DILI.

ferritinophagy ferroptosis HSPA8 NCOA4

SCI

English

Corresponding

Gastroenterology & Hepatology

Gastroenterology & Hepatology

WOS:000871869300001

WILEY

CLINICAL MEDICINE

Web of Science

1.Cent South Univ, Xiangya Sch Med, Zhuzhou Hosp, Dept Infect Dis, Chang Jiang Nan Lu 116, Zhuzhou 412007, Hunan, Peoples R China
2.Southern Univ Sci & Technol, Affiliated Hosp 2, Dept Liver Dis, Hosp Shenzhen 3, Shenzhen 518100, Guangdong, Peoples R China

Zhou, Juan,Tan, Yingzheng,Hu, Lingli,et al. Inhibition of HSPA8 by rifampicin contributes to ferroptosis via enhancing autophagy[J]. LIVER INTERNATIONAL,2022.

Zhou, Juan.,Tan, Yingzheng.,Hu, Lingli.,Fu, Jingli.,Li, Dan.,...&Long, Yunzhu.(2022).Inhibition of HSPA8 by rifampicin contributes to ferroptosis via enhancing autophagy.LIVER INTERNATIONAL.

Zhou, Juan,et al."Inhibition of HSPA8 by rifampicin contributes to ferroptosis via enhancing autophagy".LIVER INTERNATIONAL (2022).